Novel compounds

ABSTRACT

The invention provides compounds of general formula (I) wherein m, n, Z 1 , Z 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are as defined in the specification, process for their preparation, pharmaceutical compositions containing them and their use in therapy.

[0001] The present invention relates to novel compounds, processes fortheir preparation, pharmaceutical compositions containing them and theiruse in therapy.

[0002] Chemokines play an important role in immune and inflammatoryresponses in various diseases and disorders, including asthma andallergic diseases, as well as autoimmune pathologies such as rheumatoidarthritis and atherosclerosis. These small secreted molecules are agrowing superfamily of 8-14 kDa proteins characterised by a conservedfour cysteine motif. The chemokine superfamily pan be divided into twomain groups exhibiting characteristic structural motifs, the Cys-X-Cys(C-X-C) and Cys-Cys (C-C) families. These are distinguished on the basisof a single amino acid insertion between the NHl-proximal pair ofcysteine residues and sequence similarity.

[0003] The C-X-C chemokines include several potent chemoattractants andactivators of neutrophils such as interleukin-8 (IL-8) andneutrophil-activating peptide 2 (NAP-2).

[0004] The C-C chemokines include potent chemoattractants of monocytesand lymphocytes but not neutrophils such as human monocyte chemotacticproteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation,Normal T Expressed and Secreted), eotaxin and the macrophageinflammatory proteins 1ax and 1I (MIP-lI and MIP-1).

[0005] Studies have demonstrated that the actions of the chemokines aremediated by subfamilies of G protein-coupled receptors, among which arethe receptors designated CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5,CCR6, CCR7, CCR8, CCR9, CCRIO, CXCRI, CXCR2, CXCR3 and CXCR4. Thesereceptors represent good targets for drug development since agents whichmodulate these receptors would be useful in the treatment of disordersand diseases such as those mentioned above.

[0006] In accordance with the present invention, there is thereforeprovided a compound of general formula

[0007] wherein:

[0008] m is 0, 1,2or3;

[0009] each R¹ independently represents halogen, cyano, nitro, carboxyl,hydroxyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxycarbonyl, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, -NR⁹R¹⁰, C₃-C₆ cycloalkylamino, C₁-C₆alkylthio, C₁-C₆ alkylcarbonyl, C₁-C₆ alkylcarbonylamino, sulphonamido(-SO₂NH₂), C₁-C₆ alkylsulphonyl, -C(O)NR R , -NR c(o)-(NH)pR , phenyl,or C₁-C₆ alkyl optionally substituted by carboxyl or C₁-C₆alkoxycarbonyl;

[0010] p is O or 1;

[0011] X represents an oxygen atom or a CH₂, OCH₂, CH₂O, CH₂NH, NH,carbonyl or sulphonyl group and Y represents a nitrogen atom or a CH orC(OH) group, provided that when X represents an oxygen atom or a CH₂O,CH₂NH or NH group, then Y represents a CH group;

[0012] Z¹ represents a bond or a group (CH₂)q where q is 1 or 2;

[0013] Z² represents a bond or a group CH₂, with the proviso that Z andZ do not both simultaneously represent a bond;

[0014] Q represents an oxygen or sulphur atom or a group CH₂ or NH;

[0015] R² represents a group

[0016] n is 0, 1 or 2;

[0017] each R³ independently represents a C₁-C₆ alkyl, C₁-C₆alkoxycarbonyl, -CH₂OH or carboxyl group;

[0018] R⁴, R^(5,) R⁶ and R⁷ each independently represent a hydrogen atomor a C₁-C₆ alkyl group, or R⁴, R⁵, R⁶ and R⁷ together represent a C₁-C₄alkylene chain linking the two carbon atoms to which they are attachedto form a 4- to 7-membered saturated carbocycle, or R^(5,) R⁶ and R⁷each represent a hydrogen atom and R⁴ and R⁸ together with the carbonatoms to which they are attached form a 5- to 6-membered saturatedcarbocycle;

[0019] R⁸ represents a hydrogen atom, a C₁-C₆ alkyl group or is linkedto R⁴ as defined above;

[0020] R⁹ and R¹⁰ each independently represent a hydrogen atom or aC₁-C₆ alkyl group, or R⁹ and R¹⁰ together with the nitrogen atom towhich they are attached form a 4- to 7-membered saturated heterocycle;

[0021] R¹¹ and R¹² each independently represent a hydrogen atom or aC₁-C₆ alkyl group optionally substituted by C₁-C₆ alkoxycarbonyl;

[0022] R¹³ represents a hydrogen atom or a C₁-C₆ alkyl group;

[0023] R¹⁴ represents a hydrogen atom, or a C₁-C₆ alkyl group optionallysubstituted by carboxyl, C₁-C₆ alkoxy or C₁-C₆ alkoxycarbonyl;

[0024] R¹⁵ represents a group C₂-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆cycloalkyl, C₅-C₆ cycloalkenyl, adamantyl, phenyl or a saturated orunsaturated 5- to 10-membered heterocyclic ring system comprising atleast one heteroatom selected from nitrogen, oxygen and sulphur, whereineach group may be optionally substituted by one or more substituentsindependently selected from nitro, hydroxyl, oxo, halogen, carboxyl,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, Cl-C₆ alkylcarbonyl, C₁-C₆alkoxycarbonyl, phenyl and -NHC(O)-R¹⁷, with the proviso that R¹⁵ doesnot represent an unsubstituted 1-pyrrolidinyl, an unsubstituted1-piperidinyl or an unsubstituted 1-hexamethyleneiminyl(1-homopiperidinyl) group;

[0025] t is 0, 1, 2 or3;

[0026] each R¹⁶independently represents halogen, cyano, nitro, carboxyl,hydroxyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxycarbonyl, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, -NR¹⁸R¹⁹, C₃-C₆ cycloalkylamino, C₁-C₆alkylthio, C₁-C₆ alkylcarbonyl, C₁-C₆ alkylcarbonylamino, sulphonamido(-SO₂NH₂), C₁-C₆ alkylsulphonyl, -C(O)NR²⁰R^(21,) -NR²²C(o)(NH)R23,phenyl, or C₁-C₆ alkyl optionally substituted by carboxyl or C₁-C₆alkoxycarbonyl;

[0027] R¹⁷ represents a C₁-C₆ alkyl, amino (-NH₂) or phenyl group;

[0028] R¹⁸ and R¹⁹ each independently represent a hydrogen atom or aC₁-C₆ alkyl group, or R18and R¹⁹ together with the nitrogen atom towhich they are attached form a 4- to 7-membered saturated heterocycle;

[0029] R²⁰ and R²¹ each independently represent a hydrogen atom or aC₁-C₆ alkyl group optionally substituted by C₁-C₆ alkoxycarbonyl;

[0030] v is 0 or 1;

[0031] R²² represents a hydrogen atom or a C₁-C₆ alkyl group; and

[0032] R²³ represents a hydrogen atom, or a C₁-C₆ alkyl group optionallysubstituted by carboxyl, C₁-C₆ alkoxy or C₁-C₆ alkoxycarbonyl; or apharmaceutically acceptable salt or solvate thereof.

[0033] In the context of the present specification, an alkyl or alkenylsubstituent group or an alkyl or alkenyl moiety in a substituent groupmay be linear or branched. In the definition of R¹⁵, it should be notedthat the unsaturated 5- to 10-membered heterocyclic ring system may bealiphatic or aromatic.

[0034] The integer m is preferably 1 or 2.

[0035] Each R¹ independently represents halogen (e.g. chlorine,fluorine, bromine or iodine), cyano, nitro, carboxyl, hydroxyl, C₃-C₆cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C₁-C₆,preferably C₁-C₄, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy),C₁-C₆, preferably C₁-C₄, alkoxycarbonyl (e.g. methoxycarbonyl orethoxycarbonyl), C₁-C₆, preferably C₁-C₄, haloalkyl (e.g.trifluoromethyl), C₁-C₆, preferably C₁-C₄, haloalkoxy (e.g.trifluoromethoxy), -NR⁹R¹⁰, C₃-C₆ cycloalkylamino (e.g.cyclopropylamino, cyclobutylamino, cyclopentylamino or cyclohexylamino),C₁-C₆, preferably C₁-C₄, alkylthio (e.g. methylthio or ethylthio),C₁-C₆, preferably C₁-C₄, alkylcarbonyl (e.g. methylcarbonyl,ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl,n-pentylcarbonyl or n-hexylcarbonyl), C₁-C₆, preferably C₁-C₄,alkylcarbonylamino (e.g. methylcarbonylamino or ethylcarbonylamino),sulphonamido, C₁-C₆, preferably C₁-C₄, alkylsulphonyl (e.g.methylsulphonyl, ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl,n-butylsulphonyl, n-pentylsulphonyl or n-hexylsulphonyl), -C(O)NR¹¹R¹²,-NR¹³C(O)-(NH)_(p)R¹⁴, phenyl, or C₁-C₆, preferably C₁-C₄, alkyl (e.g.methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-pentyl or n-hexyl) optionally substituted by carboxyl or C₁-C₆,preferably C₁-C₄, alkoxycarbonyl (e.g. methoxycarbonyl orethoxycarbonyl).

[0036] Most preferably, each R¹ independently represents halogen(particularly chlorine or fluorine), cyano, nitro, C₁-C₆ alkoxy(especially methoxy), C₁-C₆ alkylcarbonyl (especially methylcarbonyl) orC₁-C₆ alkylcarbonylamino (particularly methylcarbonylamino). Each R¹especially represents halogen or cyano.

[0037] Preferably X represents an oxygen atom or a CH₂ or NH group.

[0038] Preferred combinations of Y, Z¹ and Z² include: Y Z¹ Z² CH CH₂bond CH bond CH₂ CH CH₂ CH₂ CH (CH₂)₂ bond N CH₂ CH₂

[0039] Q preferably represents an oxygen atom.

[0040] Each R³ independently represents a C₁-C₆, preferably C₁-C₄, alkyl(e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-pentyl or n-hexyl), C₁-C₆, preferably C₁-C₄, alkoxycarbonyl (e.g.methoxycarbonyl or ethoxycarbonyl), -CH₂OH or carboxyl group. It ispreferred that R³ represents a methyl, methoxycarbonyl, ethoxycarbonyl,-CH₂OH or carboxyl group.

[0041] R⁴, R⁵, R⁶ and R⁷ each independently represent a hydrogen atom ora C₁-C₆, preferably C₁-C₄, alkyl (e.g. methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), orR^(4,) R^(5,) R⁶ and R⁷ together represent a C₁-C₄ alkylene chainlinking the two carbon atoms to which they are attached to form a 4- to7-membered saturated carbocycle (e.g. cyclohexyl or preferablycyclopentyl), or R⁵, R⁶ and R⁷ each represent a hydrogen atom and R⁴ andR⁸ together with the carbon atoms to which they are attached form a 5-to 6-membered saturated carbocycle (preferably cyclopentyl).

[0042] R⁸ represents a hydrogen atom, a C₁-C₆, preferably C₁-C₄, alkylgroup (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, n-pentyl or n-hexyl) or is linked to R⁴ as defined above.

[0043] R⁹ and R¹⁰ each independently represent a hydrogen atom or aC₁-C₆, preferably C₁-C₄, alkyl group (e.g. methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), or R⁹and R¹⁰ together with the nitrogen atom to which they are attached forma 4- to 7-membered saturated heterocycle.

[0044] R¹l and R¹² each independently represent a hydrogen atom or aC₁-C₆, preferably C₁-C₄, alkyl group (e.g. methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl)optionally substituted by a C₁-C₆, preferably C₁-C₄, alkoxycarbonylsubstituent group.

[0045] R¹³ represents a hydrogen atom or a C₁-C₆, preferably C₁-C₄,alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, n-pentyl or n-hexyl). R¹⁴ represents a hydrogen atom, or aC₁-C₆, preferably C₁-C₄, alkyl group (e.g. methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl)optionally substituted by carboxyl, C₁-C₆, preferably C₁-C₄, alkoxy orC₁-C₆, preferably C₁-C₄, alkoxycarbonyl.

[0046] R¹⁵ represents a group C₂-C₆, preferably C₂-C₄, alkyl group (e.g.ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or n-pentyl),C₂-C₆, preferably C₂-C₄, alkenyl, C₃-C₆ cycloalkyl (e.g. cyclobutyl orcyclopentyl), C₅-C₆ cycloalkenyl, adamantyl, phenyl or a saturated orunsaturated 5- to 10-membered heterocyclic ring system comprising atleast one heteroatom selected from nitrogen, oxygen and sulphur, whereineach group may be optionally substituted by one or more (e.g. one, two,three or four) substituents independently selected from nitro, hydroxyl,oxo, halogen (e.g; fluorine, chlorine, bromine or iodine), carboxyl,C₁-C₆, preferably C₁-C₄, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), C₁-C₆, preferablyC₁-C₄, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), C₁-C₆,preferably C₁-C₄, alkylthio (e.g. methylthio or ethylthio), C₁-C₆,preferably C₁-C₄, alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl,n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonylor n-hexylcarbonyl), C₁-C₆, preferably C₁-C₄, alkoxycarbonyl (e.g.methoxycarbonyl or ethoxycarbonyl), phenyl and -NHC(O)-R¹⁷.

[0047] The saturated or unsaturated 5- to 10-membered heterocyclic ringsystem may be monocyclic or polycyclic (e.g. bicyclic) and may compriseup to four heteroatoms independently selected from nitrogen, oxygen andsulphur. Examples of ring systems that may be used include pyrrolidinyl,piperidinyl, pyrazolyl, thiazolidinyl, thienyl, isoxazolyl,thiadiazolyl, pyrrolyl, furanyl, thiazolyl, indolyl, quinolinyl,benzimidazolyl, triazolyl, tetrazolyl and pyridinyl.

[0048] Each R¹⁶ independently represents halogen (e.g. chlorine,fluorine, bromine or iodine), cyano, nitro, carboxyl, hydroxyl, C₃-C₆cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C₁-C₆,preferably C₁-C₄, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy),C₁-C₆, preferably C₁-C₄, alkoxycarbonyl (e.g. methoxycarbonyl orethoxycarbonyl), C₁-C₆, preferably C₁-C₄, haloalkyl (e.g.trifluoromethyl), C₁-C₆, preferably C₁-C₄, haloalkoxy (e.g.trifluoromethoxy), -NR¹ R¹⁹ C₃-C₆ cycloalkylamino (e.g.cyclopropylamino, cyclobutylamino, cyclopentylamino or cyclohexylamino),C₁-C₆, preferably C₁-C₄, alkylthio (e.g. methylthio or ethylthio),C₁-C₆, preferably C₁-C₄, alkylcarbonyl (e.g. methylcarbonyl,ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl,n-pentylcarbonyl or n-hexylcarbonyl), C₁-C₆, preferably C₁-C₄,alkylcarbonylamino (e.g. methylcarbonylamino or ethylcarbonylamino),sulphonamido, C₁-C₆, preferably C₁-C₄, alkylsulphonyl (e.g.methylsulphonyl, ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl,n-butylsulphonyl, n-pentylsulphonyl or n-hexylsulphonyl), -C(O)NR²¹R²²,-NR C(O)-(NH)_(v)R^(24,) phenyl, or C₁-C₆, preferably C₁-C₄, alkyl (e.g.methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, is tert-butyl,n-pentyl or n-hexyl) optionally substituted by carboxyl or C₁-C₆,preferably C₁-C₄, alkoxycarbonyl (e.g. methoxycarbonyl orethoxycarbonyl).

[0049] Preferably, each R¹⁶ independently represents halogen(particularly chlorine or fluorine), cyano, C₁-C₄ alkoxy (especiallymethoxy), C₁-C₄ alkoxycarbonyl (especially methoxycarbonyl), C₁-C₄haloalkyl (especially trifluoromethyl), C₁-C₄ alkylcarbonyl(particularly methylcarbonyl), phenyl or C₁-C₄ alkyl (e.g. methyl ortert-butyl). Each R¹⁶ is especially a halogen atom or methyl group.

[0050] R¹⁷ represents a C₁-C₆, preferably C₁ -C₄, alkyl group (e.g.methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-pentyl or n-hexyl), amino or phenyl group.

[0051] R¹⁸ and R¹⁹ each independently represent a hydrogen atom or aC₁-C₆, preferably C₁-C₄, alkyl group (e.g. methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), or R19and Rle together with the nitrogen atom to which they are attached forma 4- to 7-membered saturated heterocycle.

[0052] R²⁰ and R²¹ each independently represent a hydrogen atom or aC₁-C₆, preferably C₁-C₄, alkyl group (e.g. methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl)optionally substituted by a C₁-C₆, preferably C₁-C₄, alkoxycarbonylsubstituent group.

[0053] R²² represents a hydrogen atom or a C₁-C₆, preferably C₁-C₄,alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, n-pentyl or n-hexyl).

[0054] R²³ represents a hydrogen atom, or a C₁-C₆, preferably C₁-C₄,alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, n-pentyl or n-hexyl) optionally substituted by carboxyl,C₁-C₆, preferably C₁-C₄, alkoxy or C₁-C₆, preferably C₁-C₄,alkoxycarbonyl.

[0055] Preferred compounds of the invention include:

[0056] N-(5-Chloro-2- {3-[3-(4-chloro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy}-phenyl)-isobutyramide,

[0057] Thiophene-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,

[0058]N-[(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenylcarbamoyl)-methyl]-benzamide,

[0059] Pyrazine-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,

[0060] Cyclohexanecarboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amnide,

[0061]N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-phthalamicacid methyl ester,

[0062]N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide,

[0063]N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-urcido-acetamide,

[0064]4-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-butyramide,

[0065] 1-Acetyl-piperidine-4-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy3-phenyl)-amide,

[0066] N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methoxy-benzamide,

[0067] 2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide,

[0068] 2-Acetylarnino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide,

[0069] Adamantane-1-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,

[0070] 2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy}-phenyl)-3-phenyl-propionamide,

[0071] N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-methoxy-benzamide,

[0072] 5-Methyl-thiophene-2-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,

[0073] 1-Acetyl-pyrrolidine-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,

[0074] 1,5-Dimethyl-1H-pyrazole-3-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,

[0075] 5-Oxo-pyrrolidine-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,

[0076] 1H-Indole-6-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,Cyclobutanecarboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,

[0077] N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy-phenyl)-propionamide, Pentanoic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,

[0078] Pent-4-enoic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,

[0079] Cyclopentanecarboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy}-phenyl)-amide,

[0080] Cyclopropanecarboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,

[0081]N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-isobutyramide,

[0082] N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-ylj-2-hydroxy-propoxy}-phenyl)-2-methylsulfanyl-acetamide,

[0083]2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide,

[0084] N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1-y]]-2-hydroxy-propoxy}-phenyl)-butyramide,

[0085] N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide,

[0086] N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy}-phenyl)-2-methoxy-acetamide,

[0087] N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy}-phenyl)-2,2-dimethyl-propionamide,

[0088] 5-Oxo-hexanoic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,

[0089] Hexanoic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,

[0090] 2-Chloro-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide,

[0091] 3-Chloro-N-(2- {3-[3-(4-chioro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide,

[0092](4R)-N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-1,3-thiazolidine-4-carboxamideditrifluoroacetate,

[0093] Thiophene-2-carboxylic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin- 1-yl]-2-hydroxy-propoxy}-phenyl)-amide,

[0094]N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide,

[0095]N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-nicotinamide,

[0096] Pyridine-2-carboxylic acid(2-13-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,

[0097] N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-isonicotinamide,

[0098] Cyclohexanecarboxylic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,

[0099]N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide,

[0100] 5-Methyl-thiophene-2-carboxylic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,

[0101] Cyclobutanecarboxylic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,

[0102]N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide,

[0103] Pentanoic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,

[0104] Pent-4-enoic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,

[0105] Cyclopentanecarboxylic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,

[0106] N-(2- {3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide,

[0107] N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-2,2,2-trifluoroacetamidehydrochloride,

[0108]4-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperndin-1-yl]-2-hydroxy-propoxy}-phenylcarbamoyl)-3-methyl-butyricacid,

[0109] N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin- 1-yl]-2-hydroxy-propoxy}-phenyl)-succinamic acid,

[0110] Furan-2-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0111] 1H-Pyrrole-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0112] Thiophene-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0113] Cyclopentanecarboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0114] 5-Methyl-thiophene-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0115] 3-Chloro-thiophene-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0116] 5-Methyl-isoxazole-4-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0117] [1,2,3]Thiadiazole-4-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0118] 3-Methyl-furan-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0119] Cyclopent-1-enecarboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0120] 2-Methyl-furan-3-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0121] 3-Methyl-thiophene-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0122] 5-Nitro-lH-pyrazole-3-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0123] Thiophene-3-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0124] Cyclobutanecarboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0125] Furan-2-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0126] 1H-Pyrrole-2-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0127] Thiophene-2-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0128] 3-Chloro-thiophene-2-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0129] 5-Methyl-isoxazole-4-carboxylic acid (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0130] 3-Methyl-fiuran-2-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0131] Cyclopent- 1-enecarboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0132] 2-Methyl-furan-3-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0133] 3-Methyl-thiophene-2-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0134] 5-Chloro-thiophene-2-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0135] Thiophene-3-carboxylic acid (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0136] 2,5-Dimethyl-furan-3-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0137] Cyclobutanecarboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroky-propoxy}-4-methyl-phenyl)-amide,

[0138] Furan-3-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,

[0139]N-{2-[(3-{3-[(4-fluorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-1H-pyrrole-2-carboxamide,

[0140]N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-3-thiophenecarboxamide,

[0141]N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-2-methylpropyl)oxy]phenyl}-2-thiophenecarboxamide,compound with trifluoroacetic acid,

[0142]N-{2-[(3-{3-[(4-fluorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-2-thiophenecarboxamide,

[0143]N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]phenyl}-2-furancarboxamide,

[0144]N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]phenyl}-1-pyrrole-2-carboxamide,

[0145]N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-1H-pyrrole-3-carboxamide,

[0146]N-{2-[(3-{3-[(4-fluorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-2-furancarboxamide,

[0147]N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-2-methylpropyl)oxy]phenyl}cyclopentanecarboxamide, compound with trifluoracetic acid,

[0148]N-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1--yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide,

[0149]N-(2-3{3-[3-(4-Cyano-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide,

[0150]N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide,

[0151]N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide,and

[0152]N-(2-{3-[4-(3,4-Dichloro-phenylamino)-piperidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide.

[0153] The present invention further provides a process for thepreparation of a compound of formula (I) as defined above whichcomprises reacting a compound of general formula

[0154] or a salt thereof (e.g. an acid addition salt such as ahydrochloride salt), wherein m, n, t, R¹, R^(3,) R⁴, R⁵, R^(6,) R^(7,)R⁸, R¹⁶, Q, Z and Z are as defined in formula (I), with a compound ofgeneral formula

R¹⁵- CO₂H (IU)

[0155] or chemically equivalent derivative thereof (e.g. acyl halide oranhydride derivative) wherein 15 is as defined in formula (I);

[0156] and optionally thereafter forming a pharmaceutically acceptablesalt or solvate of the compound of formula (I) obtained.

[0157] The process of the invention may conveniently be carried out in asolvent, e.g. an organic solvent such as an alcohol (e.g. methanol orethanol), a hydrocarbon (e.g. toluene), an amine (e.g. triethylamine ordiisopropylethylamine) or acetonitrile at a temperature of, for example,15° C. or above, such as a temperature in the range from 20 to 120° C.

[0158] Compounds of formulae (II) and (III) are either commerciallyavailable, are well known in the literature or may be prepared easilyusing known techniques.

[0159] It will be appreciated by those skilled in the art that in theprocess of the present invention certain functional groups such ashydroxyl or amino groups in the starting reagents or intermediatecompounds may need to be protected by protecting groups. Thus, thepreparation of the compounds of formula (1) may involve, at anappropriate stage, the removal of one or more protecting groups.

[0160] The protection and deprotection of functional groups is describedin ‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie,Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 2ndedition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).

[0161] The compounds of formula (I) above may be converted to apharmaceutically acceptable salt or solvate thereof, preferably an acidaddition salt such as a hydrochloride, hydrobromide, phosphate, acetate,fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate orp-toluenesulphonate.

[0162] Compounds of formula (I) are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses the use of all geometric and optical isomers of thecompounds of formula (I) and mixtures thereof including racemates. Theuse of tautomers and mixtures thereof also form an aspect of the presentinvention.

[0163] The compounds of formula (I) have activity as pharmaceuticals, inparticular as modulators of chemokine receptor (especially MIP-1αchemokine receptor) activity, and may be used in the treatment ofautoinmnune, inflammatory, proliferative and hyperproliferative diseasesand immunologically-mediated diseases including rejection oftransplanted organs or tissues and Acquired Immunodeficiency Syndrome(AIDS).

[0164] Examples of these conditions are:

[0165] (1) (the respiratory tract) airways diseases including chronicobstructive pulmonary disease (COPD) such as irreversible COPD; asthma,such as bronchial, allergic, intrinsic, extrinsic and dust asthma,particularly chronic or inveterate asthma (e.g. late asthma and airwayshyper-responsiveness); bronchitis; acute, allergic, atrophic rhinitisand chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis,rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa;membranous rhinitis including croupous, fibrinous and pseudomembranousrhinitis and scrofoulous rhinitis; seasonal rhinitis including rhinitisnervosa (hay fever) and vasomotor rhinitis; sarcoidosis, farmer's lungand related diseases, fibroid lung and idiopathic interstitialpneumonia;

[0166] (2) (bone and joints) rheumatoid arthritis, seronegativespondyloarthropathies (including ankylosing spondylitis, psoriaticarthritis and Reiter's disease), Behcet's disease, Sjogren's syndromeand systemic sclerosis;

[0167] (3) (skin) psoriasis, atopical dermatitis, contact dermatitis andother eczmatous dermitides, seborrhoetic dermatitis, Lichen planus,Pemphigus, bullous Pemphigus, Epidermolysis bullosa, urticaria,angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis,Alopecia areata and vernal conjunctivitis;

[0168] (4) (gastrointestinal tract) Coeliac disease, proctitis,eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerativecolitis, food-related allergies which have effects remote from the gut,e.g., migraine, rhinitis and eczema;

[0169] (5) (other tissues and systemic disease) multiple sclerosis,atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), lupuserythematosus, systemic lupus, erythematosus, Hashimoto's thyroiditis,myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophiliafascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome andidiopathic thrombocytopenia pupura;

[0170] (6) (allograft rejection) acute and chronic following, forexample, transplantation of kidney, heart, liver, lung, bone marrow,skin and cornea; and chronic graft versus host disease;

[0171] (7) cancers, especially non-small cell lung cancer (NSCLC) andsquamous sarcoma;

[0172] (8) diseases in which angiogenesis is associated with raisedchemokine levels (e.g. NSCLC); and

[0173] (9) cystic fibrosis, stroke, re-perfusion injury in the heart,brain, peripheral limbs and sepsis.

[0174] Thus, the present invention provides a compound of formula (I),or a pharmaceutically-acceptable salt or solvate thereof, ashereinbefore defined for use in therapy.

[0175] In a further aspect, the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined in the manufacture of amedicament for use in therapy.

[0176] In the context of the present specification, the term “therapy”also includes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

[0177] The invention also provides a method of treating an inflammatorydisease in a patient suffering from, or at risk of, said disease, whichcomprises administering to the patient a therapeutically effectiveamount of a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, as hereinbefore defined.

[0178] The invention still farther provides a method of treating anairways disease in a patient suffering from, or at risk of, saiddisease, which comprises administering to the patient a therapeuticallyeffective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, as hereinbefore defined.

[0179] For the above-mentioned therapeutic uses the dosage administeredwill, of course, vary with the compound employed, the mode ofadministration, the treatment desired and the disorder indicated. Thedaily dosage of the compound of formula (I) may be in the range from0.001 mg/kg to 30 mg/kg.

[0180] The compounds of formula (I) and pharmaceutically acceptablesalts and solvates thereof may be used on their own but will generallybe administered in the form of a pharmaceutical composition in which theformula (I) compound/salt/solvate (active ingredient) is in associationwith a pharmaceutically acceptable adjuvant, diluent or carrier.Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99%w (percent by weight), morepreferably from 0.05 to 80%w, still more preferablyfrom 0.10 to 70%w,and even more preferably from 0.10 to 50%w, of active ingredient, allpercentages by weight being based on total composition.

[0181] The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, as hereinbefore defined, in association with apharmaceutically acceptable adjuvant, diluent or carrier.

[0182] The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined, with a pharmaceuticallyacceptable adjuvant, diluent or carrier.

[0183] The pharmaceutical compositions may be administered topically(e.g. to the lung and/or airways or to the skin) in the form ofsolutions, suspensions, heptafluoroalkane aerosols and dry powderformulations; or systemically, e.g. by oral administration in the formof tablets, capsules, syrups, powders or granules, or by parenteraladministration in the form of solutions or suspensions, or bysubcutaneous administration or by rectal administration in the form ofsuppositories or transdermally.

[0184] The invention will now be further explained by reference to thefollowing illustrative examples, in which ¹H NMR spectra were recordedon Varian Unity Inova 400. The central solvent peak of chloroform-d(δ^(H)7.27 ppm) were used as internal standard. Low resolution massspectra and accurate mass determination were recorded on aHewlett-Packard 100 LC-MS system equipped with APCI/ESI ionisationchambers. All solvents and commercial reagents were laboratory grade andused as received. The nomenclature used for the compounds was generatedwith ACD/IUPAC Name Pro. The following abbreviations are used in theexamples:

[0185] NMP: 1-Methyl-2-pyrrolidinone

[0186] DIEA: N,N-Diisopropylethylamine

[0187] HBTU: 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate

[0188] HoBT: 1-Hydroxybenzotriazole

[0189] THF: Tetrahydrofuran

EXAMPLE 1

[0190]N-(5-Chloro-2-13-[3-(4-chloro-phenoxy)-pyrrolidin-1-yll-2-hydroxy-propoxy)-phenyl)-isobutyramide

[0191] a) N-(5-Chloro-2-hydroxy-pheny)-isobutyramide

[0192] In a flask was added 4-chloro-2-aminophenol (1.2 g, 8.39 mmole)and water (25 ml). The suspension was vigorously stirred and isobutyricanhydride (1.6 ml, 10.5 mmole) was added. The mixture was heated to 60°C. for 30 minutes under vigorous stirring. The emulsion was cooled, anda precipitate was formed, which was collected through filtration. Thesolid was washed twice with water on the filter and was finally dried togive 1.4 g (78%) of the sub-title compound as a white solid. ¹H-NMR(400MHz, DMSO-d₆)δ:10.11 (1H, s); 9.12 (1H, s); 7.94 (1H, d, J2.5 Hz); 6.95(1H, dd, J 8.7 2.6 Hz); 6.84 (1H, d, J 8.5 Hz); 2.79 (1H, p, J 6.7 Hz);1.08 (6H, d, J6.8 Hz)

[0193] b) N-(5-Chloro-2-oxiranylmethoxy-phenyl)-isobutyramide

[0194] In a vial was added the compound obtained in a) (0.4 g, 1.87mmole), epibromohydrin (0.28 g, 2.06 mmole), K₂CO₃ (0.5 g, 3.7 mmole)and DMF (2 ml). The vial was sealed and heated with stirring (2 hours,60° C.). The mixture was then partitioned between EtOAc and water, andthe organic phase was washed twice with water and once with brine, andwas finally evaporated to give a brown solid. The crude epoxide waspurified on silica, to give 0.22 g (44%) of the sub-title compound as awhite solid.

[0195] c) In a vial was added the compound obtained in b) (0.026 g, 0.13mmole), 3-(4-chlorophenoxy)-pyrrolidine (0.035 g, 0.13 mmole) in ethanol(2 ml). The vial was sealed and heated with stirring at 75° C. for 3hours. The solution was allowed to cool, and the solvent was evaporated.The crude product was purified on silica, and the pure fractions werecollected. The title compound was lyophilized as the hydrochloride,giving 0.055 g (84%) as a white solid. The compound was a mixture offour stereoisomers, which had an effect on the NMR-spectra.

[0196] H-vNMR (400 MHz, DMSO-d₆)δ:10.84-10.34 (1H, m); 9.12 (1H, s);8.09 (1H, s); 7.36 (2H, dd, J9.2 1.3 Hz); 7.11-7.00 (3H, m); 7.00 (2H,d, J 8.8 Hz); 6.22-6.06 (1H, m); 5.22-5.10 (1H, m); 4.34 (1H, bs);4.08-3.96 (1.5H, m); 3.95-3.87 (1H, m); 3.83-3.66 (1.5H, m); 3.61-3.23(3H, m); 2.86 (1H, sept, J6.6 Hz); 2.64-2.51 (½H, m); 2.36-2.14 (1H, m);2.14-2.00 (½H, m); 1.08 (6H, d, J 6.7 Hz) APC₁-MS: m/z 467.2 [MH+]

[0197] Aniline Intermediate 1

[0198]1-(2-aminophenoxy)-3-14-(3,4-dichlorophenoxy)-l-piperidinyll-2-propanoldihydrochloride

[0199] N-(2- {3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide (1.418g, 3.13 mmol,prepared by analogy to Example 1) was dissolved in 50 ml HC₁(35%/aq,puriss) and refluxed overnight. The product precipitated and wasfiltered and dried to give 0.835 g (65%) of the title compound.

[0200] APCI-MS m/z: 411, 413 [MH⁺] ¹H NMR (400 MHz, CDC₃): δ8.39-3.31(m, 2H), 7.3 1 (d, 1H), 7.01-6.98(m, 3H), 6.94-6.91(m, 1H), 6.75(dd,1H), 4.31(m, 1H), 4.12-4.02 (m, 2H), 3.92(dd, 1H), 2.90(m, 1H), 2.69(m,1H), 2.62-2.51(m, 2H), 2.46(dd, 1H), 2.34(m, 1H), 2.18(s, 3H),2.04-1.93(m, 2H), 1.89-1.77(m, 2H).

[0201] Aniline Intermediate 2

[0202]1-[(2-aminophenyl)oxyl-3-13-[(4-chlorophenyl)oxyl-1-pyrrolidinyl}-2-propanoldihydrochloride

[0203] Prepared according to the method described in AnilineIntermediate 1.

[0204] APCI-MS m/z: 363, 365 [MH⁺]

[0205] The intermediate anilines 1 and 2 described above were used inthe following examples.

EXAMPLE 2

[0206] Thiophene-2-carboxylic acid(2-{3-13-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

[0207] To a solution of 80 uL 0.2M 2-thiophenecarboxylic acid in NMPwere HBTU (80 uL, 0.2M/NMP) ,HoBT (80 uL, 0.2M/NMP), DIEA (30 uL,0.5M/NMP) and pyridine (30 uL, 0.5M/NMP) added and stirred for 30minutes before1-[(2-aminophenyl)oxy]-3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-propanol(75 uL, 0.2M/NMP) was added. The mixture was stirred overnight atroomtemperature before it was concentrated under reduced pressure todryness. The product was diluted with IOOOuL dichloromethane and washedwith with sat.NaHCO₃/aq (800 uL), 1.81% HCI/aq(800 uL) and sat. NaCI/aq.The organic layer was concentrated under reduced pressure to dryness andused without further purification. Yield 3.6mg, 51%

[0208] APCI-MS m/z: 473.2 [MH⁺]¹H NMR (400 MHz, CD₃OD): δ8 7.88-7.85 (d,1H), 7.74-7.65 (m, 2H), 7.34-7.28 (m, 2H), 7.27-7.21(m, 1H), 7.20-7.15(m, 1H), 7.14-7.09 (dd, 1H), 7.06-7.00 (m, 1H), 6.96-6.91 (m, 2H),5.18-5.12 (m, 1H), 4.39-4.30 (m, 1H), 4.19-3.24 (m, 9H), 2.66-2.11 (m,3H)

[0209] The following Examples 3 to 53 were prepared by methods analogousto the method described in Example 2.

EXAMPLE 3

[0210]N-[(2-{3-13-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenylcarbamoyl)-methyl]-benzamide

[0211] APC₁-MS m/z: 524.3 [MH⁺]

EXAMPLE4

[0212] Pyrazine-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

[0213] APCI-MS m/z: 469.2 [MH⁺]

EXAMPLE 5

[0214] Cyclohexanecarboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yll-2-hydroxy-propoxy}-phenyl)-amide

[0215] APCI-MS m/z: 473.3 [MH⁺]

EXAMPLE 6

[0216]N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yll-2-hydroxy-propoxy}-phenyl)-phthalamicacid methyl ester

[0217] APCI-MS m/z: 525.2 [MH⁺]

EXAMPLE 7

[0218]N-(2-{3-13-(4-Chloro-phenoxy)-pyrrolidin-1-yll-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide

[0219] APCI-MS m/z: 449.2 [MH⁺]

EXAMPLE 8

[0220]N-(2-f3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yll-2-hydroxy-propoxyl-phenyl)-2-ureido-acetamide

[0221] APCI-MS m/z: 463.2 [MR⁺]

EXAMPLE 9

[0222]4-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yll-2-hydroxy-propoxy}-phenyl)-butyramide

[0223] APCI-MS m/z: 490.3 [MH⁺]

EXAMPLE 10

[0224] 1-Acetyl-piperidine-4-carboxylic acid(2-{3-13-(4-chloro-phenoxy)-pyrrolidin-1-yll-2-hydroxy-propoxy}-phenyl)-amide

[0225] APCI-MS m/z: 516.3 [MH⁺]

EXAMPLE 11

[0226]N-(2-[3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yll-2-hydroxy-propoxyl-phenyl)-3-methoxy-benzamide

[0227] APCI-MS m/z: 497.2 [MH⁺]

EXAMPLE 12

[0228]2-Acetylamino-N-(2-13-[3-(4-chloro-phenoxy)-pyrrolidin-1-yll-2-hydroxy-propoxyl-phenyl)-3-methyl-butyramide

[0229] APCI-MS m/z: 504.3 [MH⁺]

EXAMPLE 13

[0230]2-Acetylamino-N-(2-13-[3-(4-chloro-phenoxy)-pyrrolidin-1-yll-2-hydroxy-propoxyl-phenyl)-3-hydroxy-butyramide

[0231] APCI-MS m/z: 506.2 [MH⁺]

EXAMPLE 14

[0232] Adamantane-1-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

[0233] APCI-MS m/z: 525.3 [MH⁺]

EXAMPLE 15

[0234]2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yll-2-hydroxy-propoxy}-phenyl)-3-phenyl-propionamide

[0235] APCI-MS m/z: 552.3 [MH⁺]

EXAMPLE 16

[0236]N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yll-2-hydroxy-propoxy}-phenyl)-2-methoxy-benzamide

[0237] APCI-MS rn/z: 497.2 [MH⁺]

EXAMPLE 17

[0238] 5-Methyl-thiophene-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yll-2-hydroxy-propoxy}-phenyl)-amide

[0239] APCI-MS m/z: 487.2 [MH⁺]

EXAMPLE 18

[0240] 1-Acetyl-pyrrolidine-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yll-2-hydroxy-propoxy}-phenyl)-amide

[0241] APCI-MS ni/z: 502.3 [MH⁺]

EXAMPLE 19

[0242] 1,5-Dimethyl-1H-pyrazole-3-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yll-2-hydroxy-propoxy}-phenyl)-amide

[0243] APCI-MS m/z: 485.3 [MH⁺]

EXAMPLE 20

[0244] 5-Oxo-pyrrolidine-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrroludin-1-yll-2-hydroxy-propoxy}-phenyl)-amide

[0245] APCI-MS m/z: 474.2 [MH⁺]

EXAMPLE 21

[0246] 1H-Indole-6-carboxylic acid(2-{3-[3-(⁴-chloro-phenoxy)-pyrrolidin-1-yl1-2-hydroxy-ropoxy}-phenyl)-amide

[0247] APCI-MS m/z: 506.2 [MH⁺]

EXAMPLE 22

[0248] Cyclobutanecarboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

[0249] APCI-MS m/z: 445.3 [MH⁺]

EXAMPLE 23

[0250]N-(2-(3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxyl-phenyl)propionamide

[0251] APCI-MS m/z: 419.2 [MH⁺]

EXAMPLE 24

[0252] Pentanoic acid(2-{3-13-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

[0253] APCI-MS mn/z: 447.3 [MH⁺]

EXAMPLE 25

[0254] Pent-4-enoic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

[0255] APCI-MS m/z: 445.3 [MH⁺]

EXAMPLE 26

[0256] Cyclopentanecarboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

[0257] APCI-MS m/z: 459.3 [MH⁺]

EXAMPLE 27

[0258] Cyclopropanecarboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

[0259] APCI-MS m/z: 431.2 [MH⁺]

EXAMPLE 28

[0260]N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-isobutyramideAPCI-MS m/z: 433.3 [MH⁺]

EXAMPLE 29

[0261]N-(2-{3-[3-(4-Chloro-phenoxy)-pyrroldin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-methylsulfanyl-acetamide

[0262] APCI-MS m/z: 451.2 [MH⁺]

EXAMPLE 30

[0263]2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide

[0264] APCI-MS m/z: 476.2 [MH⁺]

EXAMPLE 31

[0265]N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrofidin-1-yl]-2-hydroxy-propoxy}-phenyl)-butyramide

[0266] APCI-MS m/z: 433.3 [MH⁺]

EXAMPLE 32

[0267]N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide

[0268] APCI-MS m/z: 447.3 [MH⁺]

EXAMPLE 33

[0269]N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-methoxy-acetamide

[0270] APCI-MS m/z: 435.2 [MR^(+])

EXAMPLE 34

[0271]N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxyl-pheny})-2,2-dimethyl-propionamide

[0272] APCI-MS m/z: 447.2 [MH⁺]

EXAMPLE 35

[0273] 5-Oxo-hexanoic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

[0274] APCI-MS m/z: 475.3 [MH⁺]

EXAMPLE 36

[0275] Hlexanoic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

[0276] APCI-MS m/z: 461.3 [MH⁺]

EXAMPLE 37

[0277]2-Chloro-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide

[0278] APCI-MS m/z: 501.2, 503.2 [MH⁺]

EXAMPLE 38

[0279]3-Chloro-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide

[0280] APCI-MS m/z: 501.2, 503.2 [MH⁺]

EXAMPLE 39

[0281](4R)-N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-1.3-thiazolidine-4-carboxamideditrifluoroacetate

[0282] APCI-MS m/z: 478.2 [MH⁺]

EXAMPLE 40

[0283] Thiophene-2-carboxylic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

[0284] APCI-MS m/z: 521.0, 523.0 [MH⁺]

EXAMPLE 41

[0285]N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide

[0286] APCI-MS m/z: 515.2, 517.2[MH⁺]

EXAMPLE 42

[0287]N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-nicotinamide

[0288] APCI-MS m/z: 516.2, 518.2 [MH⁺]

EXAMPLE 43

[0289] Pyridine-2-carboxylic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

[0290] APCI-MS maz: 516.2, 518.2 [MH⁺]

EXAMPLE 44

[0291]N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-isonicotinamide

[0292] APCI-MS m/z: 516.2, 518.2 [MH⁺]

EXAMPLE 45

[0293] Cyclohexanecarboxylic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

[0294] APCI-MS m/z: 521.3, 523.3 [MH⁺]

EXAMPLE 46

[0295]N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide

[0296] APCI-MS m/z: 497.2, 499.3 [MH⁺]

EXAMPLE 47

[0297] 5-Methyl-thiophene-2-carboxylic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

[0298] APCI-MS m/z: 535.2, 537.2 [MH⁺]

EXAMPLE 48

[0299] Cyclobutanecarboxylic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

[0300] APCI-MS m/z:493.3, 495.2 [MH⁺]

EXAMPLE 49

[0301]N-(2-(3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxyl-phenyl)-propionamide

[0302] APCI-MS m/z: 467.2, 469.2 [MH⁺]

EXAMPLE 50

[0303] Pentanoic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

[0304] APCI-MS m/z: 495.3, 497.3 [MH⁺]

EXAMPLE 51

[0305] Pent-4-enoic acid(2-{3-14-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

[0306] APCI-MS m/z: 493.3 ,495.2 [MH⁺]

EXAMPLE 52

[0307] Cyclopentanecarboxylic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

[0308] APCI-MS m/z: 507.3, 509.3 [MH⁺]

EXAMPLE 53

[0309]N-(2-13-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxyl-phenyl)-3-methyl-butyramide

[0310] APCI-MS m/z: 495.3,497.3 [MH⁺]

EXAMPLE 54

[0311]N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-2,2,2-trifluoroacetamidehydrochloride

[0312] A mixture of1-(2-aminophenoxy)-3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-propanol (10mg, 0.022 mmol), dichloromethane (3 ml) and Triethyl amine was cooled inan ice bath. A solution of Trifluoro acetic anhydride (3.51 μl, 0.025mmol) in dichloromethane (2 ml) was then added and the mixture stirredat 0° C. until reaction completion. The mixture was diluted withdichloromethane, washed with 1M H₂SO₄, water, dried over natriumsulphate and concentrated to give an oil. The oil was treated with 1.0 Methereal HCl solution to give the product as solid (9 mg).

[0313] APCI-MS: m/z 459, 460 [MH⁺]

EXAMPLE 55

[0314]4-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenylcarbamoyl)-3-methyl-butyricacid

[0315]1-(2-aminophenoxy)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-propanol(75 uL, 0.2 M/NMP) was mixed with 3-methyl glutaric anhydride (3 eq, 225uL 0.2 M /NMP) to get a product containing both esther and amide. Afterevaporation of the mixture it was treated with 3 eq 0.5 M LiOH in(THF/water 1:4) for two hours at 80° C. to hydrolyse the esther. Thereaction mixture was diluted with more water (2 mL) and the desiredproduct was extracted with 5×500 uL EtOAc which was evaporated todryness.

[0316] APCI-MS m/z: 539.2, 541.2 [MH⁺]

EXAMPLE 56

[0317]N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-succinamicacid

[0318] Prepared according to the method described in Example 55.

[0319] APCI-MS m/z: 511.2, 513.2 [MH⁺]

[0320] Aniline Intermediate 3

[0321]1-(2-amino-5-methylphenoxy)-3-[3-(4-chloroplhenoxy)-1-pyrrolidinyl]-2-propanol

[0322] APCI-MS m/z: 377.2, 379.1 [MH⁺]

[0323]¹H NMR (400 MHz, CDC13): δ7.26-7.21 (m, 2H), 6.79-6.74 (m, 211),6.67-6.62 (m, 3H), 4.83-4.76 (m, 1H), 4.15-4.06 (m, 1H), 4.04-4.00 (d,2H), 3.73-3.64 (s, 2H), 3.47-3.35 (s, 1H), 3.14 -2.56 (m, 6H),2.36-2.22(m, 4H), 2.05-1.95(m, 1H)

[0324] Aniline Intermediate 4

[0325]1-(2-amino-5-methylphenoxy)-3-[3-(4-fluorophenoxy)-1-pyrrolidinyl]-2-propanol

[0326] APCI-MS mz: 361.1 [MH⁺]

[0327]¹H NMR (400 MHz, CDC13): δ7.00-6.94 (m, 2H), 6.81-6.76 (m, 2H),6.67-6.62 (m, 3H), 4.81-4.74 (m, 1I1), 4.15-4.06 (m, 1H), 4.03-3.99 (m,2H), 3.88-3.36 (m, 3H), 3.12-2.56 (m, 6H), 2.33-2.23(m, 4H),2.05-1.96(m, 1H)

[0328] The compounds of Examples 57 to 85 were prepared using one of theAniline Intermediates 3 and 4.

EXAMPLE 57

[0329] Furan-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolldin-1-yl]-2-hydroxy-propoxy}4-methyl-phenyl)-amide

[0330] APCI-MS m/z: 471.5, 473.5 [MH⁺]

EXAMPLE 58

[0331] 1H-Pyrrole-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

[0332] APCI-MS m/z: 470.5, 472.5 [MH⁺]

EXAMPLE 59

[0333] Thiophene-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

[0334] APCI-MS m/z: 487.5, 489.5 [MH⁺]

EXAMPLE 60

[0335] Cyclopentanecarboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

[0336] APCI-MS m/z: 473.6, 475.5 [MH⁺]

EXAMPLE 61

[0337] 5-Methyl-thiophene-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

[0338] APCI-MS m/z: 501.5, 503.5 [MH⁺]

EXAMPLE 62

[0339] 3-Chloro-thiophene-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

[0340] APCI-MS m/z: 521.5, 532.5 [MH⁺]

EXAMPLE 63

[0341] 5-Methyl-isoxazole-4-carboxylic acid(2-{3-13-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

[0342] APCI-MS m/z: 486.5, 488.6 [MH⁺]

EXAMPLE 64 ]

[0343] 1,2,3]Thiadiazole4-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

[0344] APCI-MS m/z: 489.5, 491.5[MH⁺]

EXAMPLE 65

[0345] 3-Methyl-furan-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

[0346] APCI-MS m/z: 485.5, 487.6 [MH⁺]

EXAMPLE 66

[0347] Cyclopent-1-enecarboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

[0348] APCI-MS m/z: 471.6, 473.6 [MH⁺]

EXAMPLE 67

[0349] 2-Methyl-furan-3-carboxylic acid(2-{3-p3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

[0350] APCI-MS m/z: 485.6, 487.6 [MH⁺]

EXAMPLE 68

[0351] 3-Methyl-thiophene-2-carboxylic acid(2-{3-13-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

[0352] APCI-MS m/z: 501.6, 503.5 [MH⁺]

EXAMPLE 69

[0353] 5-Nitro-1H-pyrazole-3-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

[0354] APCI-MS m/z: 516.5, 518.5 [MH⁺]

EXAMPLE 70

[0355] Thiophene-3-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

[0356] APCI-MS m/z: 487.5, 489.5 [MH⁺]

EXAMPLE 71

[0357] Cyclobutanecarboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

[0358] APCI-MS m/z: 459.5,461.5 [MH⁺]

EXAMPLE 72

[0359] Furan-2-carboxylic acid(2-{3-13-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

[0360] APCI-MS m/z: 455.5 [MH⁺]

EXAMPLE 73

[0361] 1H-Pyrrole-2-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

[0362] APCI-MS m/z: 454.6 [MH⁺]

EXAMPLE 74

[0363] Thiophene-2-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-Yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

[0364] APCI-MS m/z: 471.5 [MH⁺]

EXAMPLE 75

[0365] 3-Chloro-thiophene-2-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

[0366] APCI-MS in/z: 505.5, 507.5 [MH⁺]

EXAMPLE 76

[0367] 5-Methyl-isoxazole-4-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

[0368] APCI-MS m/z: 470.5 [MH⁺]

EXAMPLE 77

[0369] 3-Methyl-furan-2-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

[0370] APCI-MS m/z: 469.6 [MH⁺]

EXAMPLE 78

[0371] Cyclopent-1-enecarboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

[0372] APCI-MS m/z: 455.6 [MH⁺]

EXAMPLE 79

[0373] 2-Methyl-furan-3-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

[0374] APCI-MS m/z: 469.6 [MH⁺]

EXAMPLE 80

[0375] 3-Methyl-thiophene-2-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

[0376] APCI-MS m/z: 485.5 [MH⁺]

EXAMPLE 81

[0377] 5-Chloro-thiophene-2-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

[0378] APCI-MS m/z: 505.5, 507.5 [MH⁺]

EXAMPLE 82

[0379] Thiophene-3-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}4-methyl-phenyl)-amide

[0380] APCI-MS m/z: 471.5 [MH⁺]

EXAMPLE 83

[0381] 2,5-Dimethyl-furan-3-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

[0382] APCI-MS m/z: 483.6 [MH⁺]

EXAMPLE 84

[0383] Cyclobutanecarboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

[0384] APCI-MS m/z: 443.6 [MH⁺]

EXAMPLE 85

[0385] Furan-3-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

[0386] APCI-MS m/z: 455.5 [MH⁺]

EXAMPLE 86

[0387]N-{2-[(3-{3-[(4-fluorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-1H-pyrrole-2-carboxamide

[0388] APCI-MS: m/z 454.1 [MH⁺]

EXAMPLE 87

[0389]N-{2-[(3-{3-1(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxyl-4-methylphenyl}-3-thiophenecarboxamide

[0390] APCI-MS: m/z 471.1 [MH⁺]

EXAMPLE 88

[0391]N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-2-methylpropyl)oxy]phenyl}-2-thiophenecarboxamide,compound with trifluoroacetic acid

[0392] Aniline intermediate 3 (60 mg, 0.159 rnmol),2-thiophenecarboxylic acid (20.4 mg, 0.159 mmol) and HATU (72 mg, 0.191mmol) were stirred in dichloromethane (2 ml).

[0393] Diisopropylethylamine was added to pH 8. The mixture was stirredovernight and then concentrated. The residue was purified on silica(dichloromethane/methanol 98/2) followed by purification on C18 (2 gIsolute, acetonitrile/water 20/80 to 35/65 with 0.5% trifluoroaceticacid) to give the title compound (75 mg, 79%).

[0394]¹H-NMR (400 MHz, MeOD): δ7.86 (m, 1H), 7.72 (m, 1H), 7.50 (m, 1H),7.29 (m, 3H), 7.16 (m, 2H), 7.07 (m, IlH), 6.91 (m, 211), 5.10 (m, IlH),3.82-4.17 (m, 4H), 3.24-3.69 (m, 4H), 2.13-2.64 (m, 2H), 1.38 (m, 3H).

[0395] MS-APCI+: m/z 487 [MH⁺]

EXAMPLE 89

[0396]N-{2-[(3-13-[(4-fluorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyll-2-thiophenecarboxamide

[0397] APCI MS APCI-MS: m/z 471.1 [MH⁺]

EXAMPLE 90

[0398]N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxylphenyl}-2-furancarboxamide

[0399] APCI-MS: m/z 456.9 [MH^(+])

EXAMPLE 91

[0400]N-{2-[(3-13-[(4-chlorophenyl)oxyl-1-pyrrolidinyll-2-hydroxypropyl)oxylphenyl}-1-pyrrole-2-carboxamide

[0401] APCI-MS: m/z 456.1 [MH⁺]

EXAMPLE 92

[0402]N-{2-[(3-{3-[(4-chloropheyl)oxy]-1-pyrrolidinyl}-2hydroxypropyl)oxy]4-methylphenyl}-1H-pyrrole-3-carboxamide

[0403] APCI-MS: m/z 470.0 [MH⁺]

EXAMPLE 93

[0404]N-{2-[(3-{3-[(4-fluorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxyl-4-methylphenyl}-2-furancarboxamide

[0405] APCI-MS: m/z 455.1 [MH⁺]

EXAMPLE 94

[0406]N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-2-methylpropyl)oxylphenyl}cyclopentanecarboxamide,compound with trifluoracetic acid

[0407] The compound (80 mg, 86%) was prepared from aniline intermediate3 (60 mg, 0.159 mmol) and cyclopentanecarboxylic acid (18 μl, 0.159mmol) as described in Example 88.

[0408]¹H-NMR (400 MHz, MeOD): δ7.59 (in, 1H), 7.29 (in, 2H), 7.19 (in,1H), 7.09 (in, 1H), 6.97 (in, 3H), 5.17 (m, 1H), 3.86-4.23 (m, 4H),3.35-3.73 (m, 4H), 2.86 (in, 1H), 1.45 (bs, 3H).

[0409] MS-APCI+: nimz 473 [MH⁺]

EXAMPLE 95

[0410]N-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide

[0411] The compound was prepared using an analogous method as in Example88.

[0412] APCI-MS: m/z 465 [MH⁺]

EXAMPLE 96

[0413]N-(2-{3-[3-(4-Cyano-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide

[0414] The compound was prepared using an analogous method as in Example88.

[0415] APCI-MS: mlz 472 [MH⁺]

EXAMPLE 97

[0416]N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide

[0417] The compound was prepared using an analogous method as in Example88.

[0418] APCI-MS: m/z 529 [MH⁺]

EXAMPLE 98

[0419]N-(2-{3-[3-(4-Chloro-phenoxy)-pyrroldin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide

[0420] The compound was prepared using an analogous method as in Example88.

[0421] APCI-MS: m/z 481 [MH⁺]

EXAMPLE 99

[0422]N-(2-{3-[4-(3,4-Dichloro-phenylamino)-piperidin-1-yl]-2-hydtoxy-2-methyl-propoxy}-phenyl)-benzamide

[0423] The compound was prepared using an analogous method as in Example88.

[0424] APCI-MS: nl/z 528 [MH⁺]

[0425] THP-1 Chemotaxis Assay

[0426] Introduction

[0427] The assay measured the chemotactic response elicited by MIP-1αchemokine in the human monocytic cell line THP-1. The compounds of theExamples were evaluated by their ability to depress the chemotacticresponse to a standard concentration of MIP-1 α chemokine.

[0428] Methods

[0429] Culture of THP-1 cells

[0430] Cells were thawed rapidly at 37° C. from frozen aliquots andresuspended in a 25 cm flask containing 5 ml of RPMI-1640 mediumsupplemented with Glutamax and 10% heat inactivated fetal calf serumwithout antibiotics (RPMI+10%IJHFCS). At day 3 the medium is discardedand replaced with fresh medium.

[0431] THP-1 cells are routinely cultured in RPMI-1640 mediumsupplemented with 10% heat inactivated fetal calf serum and glutamax butwithout antibiotics. Optimal growth of the cells requires that they arepassaged every 3 days and that the minimum subculture density is 4×10+5cells/ml.

[0432] Chemotaxis assay

[0433] Cells were removed from the flask and washed by centrifugation inRPMI+10%HIFCS+glutamax. The cells were then resuspended at 2×10+7cells/ml in fresh medium (RPMI+10%HIFCS+glutamax) to which was addedcalcein-AM (5 gl of stock solution to 1 ml to give a final concentrationof 5×10⁻⁶ M). After gentle mixing the cells were incubated at 37° C. ina CO₂ incubator for 30 minutes. The cells were then diluted to 50 mlwith medium and washed twice by centrifugation at 400xg. Labelled cellswere then resuspended at a cell concentration of 1× +7 cells/ml andincubated with an equal volume of MIP-1α antagonist (10⁻¹⁰ M to 10⁻⁶ Mfinal concentration) for 30 minutes at 37° C. in a humidified CO₂incubator.

[0434] Chemotaxis was performed using Neuroprobe 96-well chemotaxisplates employing 8 μm filters (cat no. 101-8). Thirty microlitres ofchemoattractant supplemented with various concentrations of antagonistsor vehicle were added to the lower wells of the plate in triplicate. Thefilter was then carefully positioned on top and then 25μl of cellspreincubated with the corresponding concentration of antagonist orvehicle were added to the surface of the filter. The plate was thenincubated for 2 hours at 37° C. in a humidified CO₂ incubator. The cellsremaining on the surface were then removed by adsorption and the wholeplate was centrifuged at 2000 rpm for 10 minutes. The filter was thenremoved and the cells that had migrated to the lower wells werequantified by the fluorescence of cell associated calcein-AM. Cellmigration was then expressed in fluorescence units after subtraction ofthe reagent blank and values were standardized to % migration bycomparing the fluorescence values with that of a known number oflabelled cells. The effect of antagonists was calculated as % inhibitionwhen the number of migrated cells were compared with vehicle.

1. A compound of general formula

wherein: m is 0, 1, 2 or 3; each R¹ independently represents halogen,cyano, nitro, carboxyl, hydroxyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆alkoxycarbonyl, C₁-C₆ haloalkyl, to C₁-C₆ haloalkoxy, -NR⁹R¹⁰, C3-C6cycloalkylamino, C₁-C₆ alkylthio, C₁-C₆ alkylcarbonyl, C₁-C6alkylcarbonylamino, sulphonamido, C₁-C6 alkylsulphonyl, -C(O)NR¹¹R^(12 ,) -NR¹³C(O)-(NH)_(p)R¹⁴, phenyl, or C₁-C₆ alkyl optionallysubstituted by carboxyl or C₁-C₆ alkoxycarbonyl; p is 0 or 1; Xrepresents an oxygen atom or a CH₂, OCH_(2,) CH₂O, CH₂NH, NH, carbonylor sulphonyl group and Y represents a nitrogen atom or a CH or C(OH)group, provided that when X represents an oxygen atom or a CH₂O, CH₂NHor NH group, then Y represents a CH group; Z¹ represents a bond or agroup (CH₂)_(q) where q is 1 or 2; Z² represents a bond or a group CH₂,with the proviso that Z¹ and Z² do not both simultaneously represent abond; Q represents an oxygen or sulphur atom or a group CH₂ or NH; R²represents a group

n is 0, 1 or 2; each R³ independently represents a C₁-C₆ alkyl, C₁-C₆alkoxycarbonyl, -CH₂OH or carboxyl group; R⁴, R⁵, R⁶ and R⁷ eachindependently represent a hydrogen atom or a C₁-C₆ alkyl group, or R⁴,R⁵, R⁶ and R7 together represent a C₁-C₄ alkylene chain linking the twocarbon atoms to which they are attached to form a 4- to 7-memberedsaturated carbocycle, or R⁵, R⁶ and R⁷ each represent a hydrogen atomand R⁴ and R⁸ together with the carbon atoms to which they are attachedform a 5- to 6-membered saturated carbocycle; R⁵ represents a hydrogenatom, a C₁-C₆ alkyl group or is linked to R⁴ as defined above; R⁹ andR¹⁰ each independently represent a hydrogen atom or a C₁-C₆ alkyl group,or R⁹ and R¹⁰ together with the nitrogen atom to which they are attachedform a 4- to 7-membered saturated heterocycle; R¹¹ and R¹² eachindependently represent a hydrogen atom or a C₁-C₆ alkyl groupoptionally substituted by C₁-C₆ alkoxycarbonyl; R¹³ represents ahydrogen atom or a C₁-C₆ alkyl group; R¹⁴ represents a hydrogen atom, ora C₁-C₆ alkyl group optionally substituted by carboxyl, C₁-C₆ alkoxy orC₁-C₆ alkoxycarbonyl; R¹⁵ represents a group C₂-C₆ alkyl, C₂-C₆ alkenyl,C₃-C₆ cycloalkyl, C₅-C₆ cycloalkenyl, adamantyl, phenyl or a saturatedor unsaturated 5- to 10-membered heterocyclic ring system comprising atleast one heteroatom selected from nitrogen, oxygen and sulphur, whereineach group may be optionally substituted by one or more substituentsindependently selected from nitro, hydroxyl, oxo, halogen, carboxyl,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₁-C₆ alkylcarbonyl,C_(l)-C₆ alkoxycarbonyl, phenyl and -NHC(O)-R¹⁷, with the proviso thatR¹⁵ does not represent an unsubstituted 1-pyrrolidinyl, an unsubstituted1-piperidinyl or an unsubstituted 1-hexamethyleneiminyl group; t is 0,1, 2 or 3; each R⁶ independently represents halogen, cyano, nitro,carboxyl, hydroxyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆alkoxycarbonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, -NR¹⁸R¹⁹, C₃-C₆cycloalkylamino, C₁-C₆ alkylthio, C₁-C₆ alkylcarbonyl, C₁-C₆alkylcarbonylamino, sulphonamido (-SO2NH2), C₁-C₆ alkylsulphonyl,-C(O)NR²⁰R²¹, -NR²²C(o)(NH) R 3, phenyl, or C₁-C₆ alkyl optionallysubstituted by carboxyl or C₁-C₆ alkoxycarbonyl; R¹⁷ represents a C₁-C₆alkyl, amino or phenyl group; R¹⁸ and R¹⁹ each independently represent ahydrogen atom or a C₁-C₆ alkyl group, or R¹⁸ and R¹⁹ together with thenitrogen atom to which they are attached form a 4- to 7-memberedsaturated heterocycle; R²⁰ and R²¹ each independently represent-ahydrogen atom or a C₁-C₆ alkyl group optionally substituted by C₁-C₆alkoxycarbonyl; v is 0 or 1; R²² represents a hydrogen atom or a C₁-C₆alkyl group; and R23 represents a hydrogen atom, or a C₁-C₆ alkyl groupoptionally substituted by carboxyl, C₁-C₆ alkoxy or C₁-C₆alkoxycarbonyl; or a pharmaceutically acceptable salt or solvatethereof.
 2. A compound according to claim 1, wherein X represents anoxygen atom or a CH₂ or NH group.
 3. A compound according to claim 1,wherein Y represents a CH group.
 4. A compound. according to any one ofclaims 1 to 3, wherein Q represents an oxygen atom.
 5. A compoundaccording to any one of claims 1 to 4, wherein R¹⁵ represents a groupC₂-C₅ alkyl, C₂-C₄ alkenyl, C₃-C₆ cycloalkyl, C₅-C₆ cycloalkenyl,adamantyl, phenyl or a saturated or unsaturated 5- to 10-memberedheterocyclic ring system comprising at least one heteroatom selectedfrom nitrogen, oxygen and sulphur, wherein each group may be optionallysubstituted by one, two or three substituents independently selectedfrom hydroxyl, oxo, halogen, carboxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆alkylthio, C₁-C₆ alkylcarbonyl, C₁-C₆ alkoxycarbonyl, phenyl and-NHC(O)-R¹⁷.
 6. A compound according to claim 5, wherein the saturatedor unsaturated 5- to 10-membered heterocyclic ring system comprising atleast one heteroatom selected from nitrogen, oxygen and sulphur, ispyrrolidinyl, piperidinyl, pyrazolyl, thiazolidinyl, thienyl,thiadiazolyl, isoxazolyl, pyrrolyl, firanyl, thiazolyl, indolyl,quinolinyl, benzimidazolyl, triazolyl, tetrazolyl or pyridinyl.
 7. Acompound according to any one of claims 1 to 6, wherein each R¹⁶independently represents halogen, cyano, C₁-C₄ alkoxy, C₁-C₄alkoxycarbonyl, C₁-C₄ haloalkyl, C₁-C₄ alkylcarbonyl, phenyl or C₁ -C₄alkyl.
 8. A compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, as defined in claim 1 being selected from:N-(5-Chloro-2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-isobutyramide,Thiophene-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,N-[(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-l-yl]-2-hydroxy-propoxy}-phenylcarbamoyl)-methyl]-benzamide,Pyrazine-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,Cyclohexanecarboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,N-(2- {3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-phthalamic acid methyl ester, N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide, N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy}-phenyl)-2-ureido-acetamide,4-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-butyramide,1 -Acetyl-piperidine-4-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methoxy-benzamide,2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide,2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide,Adamantane-1-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-phenyl-propionamide,N-(2-{3 -[3 -(4-Chloro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy}-phenyl)-2-methoxy-benzamide,5-Methyl-thiophene-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,1-Acetyl-pyrrolidine-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,1,5-Dimethyl-1H-pyrazole-3-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,5-Oxo-pyrrolidine-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,1H-Indole-6-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,Cyclobutanecarboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide,Pentanoic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,Pent-4-enoic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,Cyclopentanecarboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,Cyclopropanecarboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-isobutyramide,N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-methylsulfanyl-acetamide,2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide,N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-butyramide,N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide,N-(2-{3-[3-(4-Chloro-phenoxy)-pyirolidin- 1-yl]-2-hydroxy-propoxy}-phenyl)-2-methoxy-acetamide,N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy}-phenyl)-2,2-dimethyl-propionamide,5-Oxo-hexanoic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,Hexanoic acid (2-{3-[3 -(4-chloro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy}-phenyl)-amide,2-Chloro-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide,3-Chloro-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide,(4R)-N-(2-{3-[3-(4-chlorophenoxy)- 1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-1,3-thiazolidine-4-carboxamideditrifluoroacetate, Thiophene-2-carboxylic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide,N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-nicotinamide,Pyridine-2-carboxylic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-isonicotinamide,Cyclohexanecarboxylic acid(2-{3-[4-(3,4-dichioro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,N-(2-{3 -[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide,5-Methyl-thiophene-2-carboxylic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,Cyclobutanecarboxylic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,N-(2- {3-[4-(3,4-Dichloro-phenoxy)-piperidin- 1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide, Pentanoic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,Pent-4-enoic acid (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin- 1-yl]-2-hydroxy-propoxy}-phenyl)-amide, Cyclopentanecarboxylic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin- 1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide,N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-2,2,2-trifluoroacetamidehydrochloride,4-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenylcarbamoyl)-3-methyl-butyricacid, N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin- 1-yl]-2-hydroxy-propoxy}-phenyl)-succinamic acid, Furan-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide, 1H-Pyrrole-2-carboxylicacid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide, Thiophene-2-carboxylicacid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide, Cyclopentanecarboxylicacid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,5-Methyl-thiophene-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,3-Chloro-thiophene-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,5-Methyl-isoxazole-4-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,3-Methyl-fuiran-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,Cyclopent-1-enecarboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,2-Methyl-furan-3-carboxylic acid (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1 -yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,3-Methyl-thiophene-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,5-Nitro- lH-pyrazole-3-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide, Thiophene-3-carboxylicacid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,Cyclobutanecarboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,Furan-2-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-1-propoxy}-4-methyl-phenyl)-amide,1H-Pyrrole-2-carboxylic acid (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide, Thiophene-2-carboxylicacid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,3-Chloro-thiophene-2-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,5-Methyl-isoxazole-4-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,3-Methyl-furan-2-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,Cyclopent-1-enecarboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,2-Methyl-fluran-3-carboxylic acid (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,3-Methyl-thiophene-2-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,5-Chloro-thiophene-2-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}4-methyl-phenyl)-amide,Thiophene-3-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,2,5-Dimethyl-furan-3-carboxylic acid (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-pheny])-amide, Cyclobutanecarboxylicacid(2-{3-[3-(4-fluoro-phenoxy)-pyirolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide, Furan-3-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,N-{2-[(3-{3-[(4-fluorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-1H-pyrrole-2-carboxamide,N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-3-thiophenecarboxamide,N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-2-methylpropyl)oxy]phenyl}-2-thiophenecarboxamide,compound with trifluoroacetic acid,N-{2-[(3-{3-[(4-fluorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-2-thiophenecarboxamide,N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]phenyl}-2-furancarboxamide,N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]phenyl}-1-pyrrole-2-carboxamideN-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl)}-2-hydroxypropyl)oxy]-4-methylphenyl}-1H-pyrrole-3-carboxamide,.N-{2-[(3-{3-[(4-fluorophenyl)oxy]-1-pyrrolidinyl)}-2-hydroxypropyl)oxy]-4-methylphenyl}-2-fuirancarboxamide,N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl)}-2-hydroxy-2-methylpropyl)oxy]phenyl}cyclopentanecarboxamide,compound with trifluoracetic acid,N-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide, N-(2-{3-[3-(4-Cyano-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide,N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide,N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide, andN-(2-{3-[4-(3,4-Dichloro-phenylamino)-piperidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide.9. A process for the preparation of a compound of formula (I) as definedin claim 1 which comprises reacting a compound of general formula

or a salt thereof, wherein m, n, t, R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁶, Q,Z¹ and Z² are as defined in formula (I), with a compound of generalformula R¹⁵-CO₂H (M) or chemically equivalent derivative thereof,wherein R¹⁵ is as defined in formula (I); and optionally thereafterforming a pharmaceutically acceptable salt or solvate of the compound offormula (I) obtained.
 10. A pharmaceutical composition comprising acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as claimed in any one of claims 1 to 8 in associationwith a pharmaceutically acceptable adjuvant, diluent or carrier.
 11. Aprocess for the preparation of a pharmaceutical composition as claimedin claim 10 which comprises mixing a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, as claimed in anyone of claims 1 to 8 with a pharmaceutically acceptable adjuvant,diluent or carrier.
 12. A compound of formula (I) or apharmaceutically-acceptable salt or solvate thereof, as claimed in anyone of claims 1 to 8 for use in therapy.
 13. Use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,as claimed in any one of claims 1 to 8 in the manufacture of amedicament for use in therapy.
 14. Use of a compound of formula (I), ora pharmaceutically acceptable salt or solvate thereof, as claimed in anyone of claims 1 to 8 in the manufacture of a medicament for thetreatment of human diseases or conditions in which modulation ofchemokine receptor activity is beneficial.
 15. Use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,as claimed in any one of claims 1 to 8 in the manufacture of amedicament for use in treating rheumatoid arthritis.
 16. Use of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as claimed in any one of claims 1 to 8 in themanufacture of a medicament for use in treating chronic obstructivepulmonary disease.
 17. Use of a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, as claimed in anyone of claims 1 to 8 in the manufacture of a medicament for use intreating asthma.
 18. Use of a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, as claimed in anyone of claims 1 to 8 in the manufacture of a medicament for use intreating multiple sclerosis.
 19. A method of treating an inflammatorydisease in a patient suffering from, or at risk of, said disease, whichcomprises administering to the patient a therapeutically effectiveamount of a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, as claimed in any one of claims 1 to
 8. 20. Amethod of treating an airways disease in a patient suffering from, or atrisk of, said disease, which comprises administering to the patient atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, as claimed in anyone of claims 1 to 8.